U.S. patent number 10,583,246 [Application Number 14/003,932] was granted by the patent office on 2020-03-10 for high flow rate isolated infusion for regional treatment of cancer and medical conditions.
This patent grant is currently assigned to H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.. The grantee listed for this patent is Stephen Stewart, Jonathan Zager. Invention is credited to Stephen Stewart, Jonathan Zager.
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United States Patent |
10,583,246 |
Zager , et al. |
March 10, 2020 |
High flow rate isolated infusion for regional treatment of cancer
and medical conditions
Abstract
The present application relates to high flow rate isolated
regional treatment of cancer and proliferative disorders and
conditions. For example, provided are methods, systems and devices
for treating a cancer in a region of a subject using high flow rate
isolated infusion.
Inventors: |
Zager; Jonathan (Tampa, FL),
Stewart; Stephen (Harmony, PA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Zager; Jonathan
Stewart; Stephen |
Tampa
Harmony |
FL
PA |
US
US |
|
|
Assignee: |
H. LEE MOFFITT CANCER CENTER AND
RESEARCH INSTITUTE, INC. (Tampa, FL)
|
Family
ID: |
46798834 |
Appl.
No.: |
14/003,932 |
Filed: |
March 9, 2012 |
PCT
Filed: |
March 09, 2012 |
PCT No.: |
PCT/US2012/028481 |
371(c)(1),(2),(4) Date: |
September 09, 2013 |
PCT
Pub. No.: |
WO2012/122475 |
PCT
Pub. Date: |
September 13, 2012 |
Prior Publication Data
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|
|
Document
Identifier |
Publication Date |
|
US 20130345675 A1 |
Dec 26, 2013 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61450895 |
Mar 9, 2011 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M
5/44 (20130101); A61M 5/142 (20130101); A61M
5/168 (20130101); A61M 5/14276 (20130101); A61M
5/16831 (20130101); A61M 5/145 (20130101) |
Current International
Class: |
A61M
5/142 (20060101); A61M 5/44 (20060101); A61M
5/168 (20060101); A61M 5/145 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
"Optimizing regional infusion treatment strategies for melanoma of
the extremities", Andrew Coleman, BSc, MA, MHS, Christina K
Augustine, PhD, Georgia Beasley, MD, Gretchen Sanders, RN,
andDouglas Tyler, MD, Expert Rev Anticancer Ther. Nov. 2009; 9(11):
1599. (Year: 2009). cited by examiner .
Brady, et al., "Isolated limb infusion with melphalan and
dactinomycin for regional melanoma and soft-tissue sarcoma of the
extremity: final report of a phase II clinical trial," Melanoma
Res., Apr. 2009, 19(2):106-111. cited by applicant .
Chai, et al., "A multi-institutional experience of repeat regional
chemotherapy for recurrent melanoma of extremities," Ann Surg
Oncol, May 2013, 19(5):1637-43. cited by applicant .
Deneve, et al., "Isolated regional therapy for advanced extremity
soft tissue sarcomas," Surg Oncol Clin N Am, Apr. 2012,
21(2):287-99. cited by applicant .
Han, et al., "Minimally invasive intra-arterial regional therapy
for metastatic melanoma: isolated limb infusion and percutaneous
hepatic perfusion," Expert Opin Drug Metab Toxicol, Nov. 2011,
7(11):1383-94. cited by applicant .
Moller, et al., "Toxicities associated with hyperthermic isolated
limb perfusion and isolated limb infusion in the treatment of
melanoma and sarcoma," Intl J Hyperthermia, May 2008, 24(3):275-89.
cited by applicant .
Santillan, et al., "Predictive Factors of Regional Toxicity and
Serum Creatine Phosphokinase Levels After Isolated Limb Infusion
for Melanoma: A Multi-Institutional Analysis," Annals Surg Oncol,
Sep. 2009, 16(9):2570-78. cited by applicant .
Turaga, et al., "Limb preservation with isolated limb infusion for
locally advanced nonmelanoma cutaneous and soft-tissue malignant
neoplasms," Arch Surg, Jul. 2011, 146(7):870-75. cited by applicant
.
Vohra, et al., "The use of isolated limb infusion in limb
threatening extremity sarcomas," Int J Hyperthermia, 2013,
29(1):1-7. cited by applicant .
Vyas, et al., "Isolated limb infusion with cytotoxic agents: A
Simplified Approach for Venous Access," Cancer, Nov. 18, 2010,
116(2):459-464. cited by applicant .
Wong, et al., "Isolated limb infusion in a series of over 100
infusions: a single-center experience," Ann Surg Oncol, Apr. 2013,
20(4):1121-27. cited by applicant .
Wong, et al., "Resection of Residual Disease after Isolated Limb
Infusion (ILI) Is Equivalent to a Complete Response after ILI-Alone
in Advanced Extremity Melanoma," Ann Surg Oncol, Feb. 2014,
21(2):650-55. cited by applicant.
|
Primary Examiner: Lee; Brandy S
Attorney, Agent or Firm: Meunier Carlin & Curfman
LLC
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application
No. 61/450,895, filed on Mar. 9, 2011, and is a 371 National phase
of PCT US2012/028481, filed Mar. 9, 2012, both of which are
incorporated by reference herein in their entirety.
Claims
What is claimed is:
1. A method for treating a cancer in a vascularly isolated region
of a subject, the vascularly isolated region being isolated by at
least one tourniquet, the method comprising: a. percutaneously
introducing a catheter into a vasculature of the subject; b.
advancing the catheter to or in proximity to the vascularly
isolated region, wherein the catheter is introduced and advanced
through an artery of the subject; and c. infusing and continuously
recirculating fluid through the catheter and into the vascularly
isolated region, wherein the fluid comprises at least one
therapeutic agent effective for treating the cancer, and wherein
the fluid is infused into the vascularly isolated region at a rate
of 160 cc/min or higher.
2. The method of claim 1 further comprising reducing or eliminating
escape of the infused fluid from the vascularly isolated
region.
3. The method of claim 2, wherein the tourniquet is applied
proximal to a location where the fluid is infused into the
vascularly isolated region from the catheter.
4. The method of claim 3, further comprising reducing flow of the
infused fluid through one or more collateral vessels in the
vascularly isolated region.
5. The method of claim 1, wherein the therapeutic agent is an
anti-cancer agent.
6. The method of claim 1, wherein the catheter is greater than 6
french in size.
7. The method of claim 6, wherein the catheter is 7, 8, 9, 10, 11
or 12 french in size or is any size in-between 7 and 12 french.
8. The method of claim 1, wherein the fluid is infused into the
vascularly isolated region at a rate of between 160 cc/min and 600
cc/min.
9. The method of claim 1, wherein the fluid is infused for at least
10 minutes.
10. The method of claim 9, wherein the fluid is infused for 10, 20,
30, 40 minutes or more.
11. A method for treating a cancer in a vascularly isolated region
of a subject, the vascularly isolated region being isolated by at
least one tourniquet, the method comprising: a. percutaneously
introducing a catheter into a vasculature of the subject remote
from the vascularly isolated region; b. advancing the catheter to
or in proximity to the vascularly isolated region; and c. infusing
and continuously recirculating fluid through the catheter and into
the vascularly isolated region, wherein the fluid comprises at
least one therapeutic agent effective for treating the cancer, and
wherein the fluid is infused into the vascularly isolated region at
a rate of 160 cc/min or higher.
12. A system for treating a cancer in a vascularly isolated region
of a subject, the vascularly isolated region being isolated by at
least one tourniquet, the system comprising: a. an intra-vascular
catheter; and b. a fluid propulsion apparatus configured to infuse
and continuously recirculate fluid through the intra-vascular
catheter and into the vascularly isolated region of the subject,
wherein the catheter is configured for percutaneous insertion into
a vasculature of the subject and wherein the fluid is infused into
the vascularly isolated region at a rate of 160 cc/min or
higher.
13. The system of claim 12, wherein the intra-vascular catheter is
further configured for insertion into the vasculature of the
subject remote from the vascularly isolated region to be
treated.
14. The system of claim 12, wherein the fluid propulsion apparatus
is a pump or a syringe.
15. The system of claim 12, wherein the fluid propulsion apparatus
is a nonocclusive pump.
16. The system of claim 12, wherein the fluid propulsion apparatus
is a pressure differential pump.
Description
TECHNICAL FIELD
The present application relates to regional treatment of cancer and
proliferative disorders and conditions.
BACKGROUND
Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are
alternative approaches for regional chemotherapy treatment.
During ILP the limb vasculature is isolated from that of the rest
of the body and a high dose of a chemotherapeutic agent (e.g.
melphalan) can be delivered to the tumor-bearing tissues. Regional
drug concentrations can be administered up to a 10-fold of what is
tolerated systemically. Due to the isolation of the limb, systemic
toxicity is absent or negligible. Isolation is achieved by ligation
or temporary occlusion of collateral blood vessels and the
placement of a proximal tourniquet. The limb blood flow is then
pumped through an oxygenator and a heat exchanger in an external
circuit to provide oxygenated and temperature regulated regional
perfusion.
The ILP technique involves a technically complex and invasive
operative procedure, requiring open surgical cannulation of the
vessels at the root of the extremity. In addition, ILP requires
expensive equipment, occupies a surgical operating room for a long
period and involves a substantial number of surgical, anesthetic
and perfusion staff and nursing personnel. It is only available in
specialized centers and is considered less appropriate in elderly
patients or those with serious medical co-morbidities.
Complications from ILP are not uncommon Significant regional
toxicity such as skin necrosis, compartment syndrome and peripheral
neuropathy can occur. Vascular catastrophe requiring arterial
reconstruction or amputation is uncommon but has been reported.
Isolated limb infusion (LIL) is a low flow, minimally invasive
alternative to open complex surgical procedure isolated limb
perfusion. Certain differences are evident: ILI is low flow,
minimally invasive percuataneous catheters, tourniquet isolation of
the extremities and is acidotic and not oxygenated. ILP is high
flow, involves an open complex surgical procedure involving open
cannulation of the vessels, it is oxygenated, and aerobic. ILI is
very repeatable, whereas ILP is difficult to repeat in the same
extremity.
SUMMARY
The present application relates to regional treatment of cancer and
proliferative disorders and conditions. For example, provided are
methods, systems and devices for treating a cancer in a region of a
subject. The example systems, methods and devices can be used as
alternatives to ILP and low flow rate ILI. For example, provided
are high flow rate ILI (HF-ILI) methods and systems.
An example method for treating a cancer in a region of a subject
includes percutaneuosly introducing a catheter into the vasculature
of the subject, advancing the catheter to, or in proximity to, the
region, and infusing fluid through the catheter and into the
region, wherein the fluid comprises at least one therapeutic agent
effective for treating the cancer. The fluid is infused into the
region at a rate of 150 cc/min or higher. Optionally, the
therapeutic agent is an anti-cancer agent. Optionally, the catheter
is introduced and advanced through an artery of the subject.
Optionally, the method further comprising reducing or eliminating
escape of the infused fluid from the region. For example, the
escape of infused fluid can be reduced or eliminated by applying a
tourniquet proximal to the location where fluid is infused into the
region from the catheter. Optionally, the method includes reducing
flow of infused fluid through one or more collateral vessels in the
region.
Optionally, the catheter is greater than 6 french in size. For
example, the catheter is optionally 7, 8, 9, 10, 11 or 12 french in
size or is any size in-between 7 and 12 french. The fluid can
infused into the region at a rate of between about 150 cc/min and
about 600 cc/min. For example, the fluid is optionally infused into
the region at 150 cc/min, 160 cc/min, 170 cc/min, 180 cc/min, 190
cc/min, 200 cc/min, 210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min,
250 cc/min, 260 cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300
cc/min, 310 cc/min, 320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min,
360 cc/min, 370 cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410
cc/min, 420 cc/min, 430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min,
470, cc/min 480 cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520
cc/min, 530 cc/min, 540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min
580 cc/min, 590 cc/min, 600 cc/min, or at rates there between.
The fluid is optionally infused, for example, at the rates
described herein, for at least 10 minutes. For example, the fluid
is optionally infused for 10, 20, 30, 40 minutes or more.
An example method for treating a cancer in a region of a subject
includes introducing a catheter into the vasculature of the subject
remote from the region, advancing the catheter to or in proximity
to the region, and infusing fluid through the catheter and into the
region. The fluid comprises at least one therapeutic agent
effective for treating the cancer and the catheter is greater than
6 french in size.
Optionally, the catheter is introduced and advanced through an
artery of the subject. Optionally, the method further comprising
reducing or eliminating escape of the infused fluid from the
region. For example, the escape of infused fluid can be reduced or
eliminated by applying a tourniquet proximal to the location where
fluid is infused into the region from the catheter. Optionally, the
method includes reducing flow of infused fluid through one or more
collateral vessels in the region.
Optionally, the catheter is greater than 6 french in size. For
example, the catheter is optionally 7, 8, 9, 10, 11 or 12 french in
size or is any size in-between 7 and 12 french. The fluid can be
infused into the region at a rate of between about 150 cc/min and
about 600 cc/min. For example, the fluid is optionally infused into
the region at 150 cc/min, 160 cc/min, 170 cc/min, 180 cc/min, 190
cc/min, 200 cc/min, 210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min,
250 cc/min, 260 cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300
cc/min, 310 cc/min, 320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min,
360 cc/min, 370 cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410
cc/min, 420 cc/min, 430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min,
470, cc/min 480 cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520
cc/min, 530 cc/min, 540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min
580 cc/min, 590 cc/min, 600 cc/min, or at rates there between.
The fluid is optionally infused, for example, at the rates
described herein, for at least 10 minutes. For example, the fluid
is optionally infused for 10, 20, 30, 40 minutes or more.
An example system for treating a cancer in a region of a subject
includes an intra-vascular catheter and a fluid propulsion
apparatus configured to move fluid through the catheter and into
the region of the subject. Optionally, the catheter is greater than
6 french in size and the catheter is configured for percutaneous
insertion into the vasculature of the subject. The catheter is
optionally 7, 8, 9, 10, 11 or 12 french in size or is any size
in-between 7 and 12 french.
Optionally, the fluid propulsion apparatus is configured to infuse
fluid into the region at a rate of between 150 cc/min and 600
cc/min or at a higher rate. For example, the fluid propulsion
apparatus is optionally configured to infuse fluid into the region
at 150 cc/min, 160 cc/min, 170 cc/min, 180 cc/min, 190 cc/min, 200
cc/min, 210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min, 250 cc/min,
260 cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300 cc/min, 310
cc/min, 320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min, 360 cc/min,
370 cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410 cc/min, 420
cc/min, 430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min, 470, cc/min
480 cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520 cc/min, 530
cc/min, 540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min 580 cc/min,
590 cc/min, 600 cc/min, or at rates there between.
The catheter is optionally configured for insertion into the
vasculature of the subject remote from the region to be treated.
Optionally, the fluid propulsion apparatus is a pump or a syringe.
For example, the fluid propulsion apparatus is optionally a
nonocclusive pump or a pressure differential pump.
A system for treating a cancer in a region of a subject includes an
arterial intra-vascular catheter and a fluid propulsion apparatus
configured to move fluid comprising a cancer therapeutic agent
through the catheter and into the region of the subject. The
catheter is greater than 6 french in size and is configured for
percutaneous insertion into the vasculature of the subject.
Optionally, the arterial catheter is 7, 8, 9, 10, 11 or 12 french
in size or is any size in-between 7 and 12 french. The system
further comprises a venous catheter. The venous catheter is
optionally 7, 8, 9, 10, 11 or 12 french in size or is any size
in-between 7 and 12 french.
The fluid propulsion apparatus is configured to infuse fluid into
the region at a rate of between 150 cc/min and 600 cc/min or at a
higher rate. For example, the fluid propulsion apparatus is
configured to infuse fluid into the region at 150 cc/min, 160
cc/min, 170 cc/min, 180 cc/min, 190 cc/min, 200 cc/min, 210 cc/min,
220 cc/min, 230 cc/min, 240 cc/min, 250 cc/min, 260 cc/min, 270
cc/min, 280 cc/min, 290 cc/min, 300 cc/min, 310 cc/min, 320 cc/min,
330 cc/min, 340 cc/min, 350 cc/min, 360 cc/min, 370 cc/min, 380
cc/min, 390 cc/min, 400 cc/min, 410 cc/min, 420 cc/min, 430 cc/min,
440 cc/min, 450 cc/min, 460 cc/min, 470, cc/min 480 cc/min, 490
cc/min, 500 cc/min, 510 cc/min, 520 cc/min, 530 cc/min, 540 cc/min,
550 cc/min, 560 cc/min, 570, cc/min 580 cc/min, 590 cc/min, 600
cc/min, or at rates there between.
Optionally, the catheter is configured for insertion into the
vasculature of the subject remote from the region to be treated.
Optionally, the fluid propulsion apparatus is a pump or a syringe.
For example, the fluid propulsion apparatus is optionally a
nonocclusive pump. The fluid propulsion apparatus is optionally a
pressure differential pump.
Also provided is a fluid circuit for delivering a cancer
therapeutic to a region of a subject. An example circuit includes a
venous catheter positionable within a vein in the region of the
subject and an arterial catheter positionable within an artery in
the region of the subject. The circuit further includes a pump in
communication with the venous catheter and arterial catheter,
wherein activation of the pump causes fluid comprising the cancer
therapeutic to circulate through the venous catheter, arterial
catheter and region of the subject at rate of 150 cc/minutes or
greater.
The venous catheter is optionally 7, 8, 9, 10, 11 or 12 french in
size or is any size in-between 7 and 12 french. The arterial
catheter is optionally 7, 8, 9, 10, 11 or 12 french in size or is
any size in-between 7 and 12 french.
The pump is optionally configured to infuse fluid into the region
at a rate of between 150 cc/min and 600 cc/min or at a higher rate.
For example, the pump is optionally configured to infuse fluid into
the region at 160 cc/min, 170 cc/min, 180 cc/min, 190 cc/min, 200
cc/min, 210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min, 250 cc/min,
260 cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300 cc/min, 310
cc/min, 320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min, 360 cc/min,
370 cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410 cc/min, 420
cc/min, 430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min, 470, cc/min
480 cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520 cc/min, 530
cc/min, 540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min 580 cc/min,
590 cc/min, 600 cc/min, or at rates there between. The pump is
optionally a nonocclusive pump. The pump is optionally a pressure
differential pump.
These and other features and advantages of the present invention
will become more readily apparent to those skilled in the art upon
consideration of the following detailed description and
accompanying drawings, which describe both the preferred and
alternative embodiments of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a schematic illustration of an example high flow rate
isolated limb infusion (HF-ILI) circuit.
FIG. 1B is a schematic illustration of an example HF-ILI
circuit.
FIG. 2 is a schematic illustration of an example pump-assisted
HF-ILI circuit.
DETAILED DESCRIPTION
The present invention now will be described more fully hereinafter
with reference to specific embodiments of the invention. Indeed,
the invention can be embodied in many different forms and should
not be construed as limited to the embodiments set forth herein;
rather, these embodiments are provided so that this disclosure will
satisfy applicable legal requirements.
As used in the specification, and in the appended claims, the
singular forms "a," "an," "the," include plural referents unless
the context clearly dictates otherwise.
The term "comprising" and variations thereof as used herein are
used synonymously with the term "including" and variations thereof
and are open, non-limiting terms.
Provided are methods for treating a cancer in a region of a
subject. Although ILP is effective in this regard, it is an
invasive, complex, and costly procedure. In response to the
difficulties associated with ILP, a simplified and minimally
invasive procedure called isolated limb infusion (ILI) was
developed with the objective of obtaining the benefits of ILP
without incurring its major disadvantages.
ILI is a non-oxygenated, low-flow, anoxic procedure performed via
percutaneously inserted catheters. Despite the brief exposure time
of the tissues to melphalan during ILI (20-30 minutes), theory and
practice have shown that there is adequate cellular drug uptake for
effective tumor cell killing to be achieved in most patients.
This disclosure is related to high flow rate ILI (HF-ILI), which
uses infusion flow rates greater than conventional ILI procedures.
An example HF-ILI method comprises percutaneuosly introducing a
catheter into the vasculature of a subject and advancing the
catheter to, or in proximity to, the region. As used throughout, by
a subject is meant an individual. A patient refers to a subject
afflicted with a disease or disorder. The term patient includes
human and veterinary subjects.
Referring to FIGS. 1A and 1B, the systems 100 and 101 comprise an
arterial catheter 104 and a venous catheter 102 that can be
advanced into a limb 116 of the subject. The limb can be an arm or
a leg. The limb can be afflicted with cancer or another
proliferative disease or disorder. The region to be treated can
also be an organ such as a liver or portion thereof that can be
vascularly isolated from the subject's systemic circulation.
Once advanced into the region, a fluid 112 comprising at least one
therapeutic agent is infused through the arterial catheter 104 and
into the region. The therapeutic agent is optionally effective for
treating the cancer. A variety of therapeutic agents can be used.
For example agents used in ILP or conventional ILI can be used with
the disclosed HF-ILI methods, systems and devices.
The specific therapeutically effective dose level for any
particular patient may depend upon a variety of factors including
the disorder being treated and the severity of the disorder;
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration; the route of
administration; the rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed and like
factors well known in the medical arts. The dosage can be adjusted
by the individual physician. Dosage can vary, and can be
administered in one or more dose administrations daily, for one or
several days. Guidance can be found in the literature for
appropriate dosages for given classes of pharmaceutical products.
The dosage can also be determined for new therapeutic agents using,
for example, the above considerations.
Optionally, the fluid is infused into the region at a rate of 150
cc/min or higher. In this regard, the methods described herein are
optionally referred to as High Flow Rate Isolated Limb Infusion
(HF-ILI), which means that flow rates of at least 150 cc/min can be
used to treat a regional lesion in a subject. Optionally, the flow
rates are constant, for example, during the duration of one or more
treatment protocols.
The arterial and/or venous catheter used for HF-ILI are optionally
greater than 6 french in size. For example, the either or both the
arterial and venous catheters are optionally 7, 8, 9, 10, 11 or 12
french in size or is any size in-between 7 and 12 french.
Optionally, the arterial and venous catheters are matched in size
such that the same size french catheter is used on the arterial and
venous sides of the circuit. Optionally, the arterial and venous
catheters differ in french size.
As noted above, the fluid can be infused at a predetermined rate.
For example, the fluid is optionally infused into the region at a
rate of between 150 cc/min and 600 cc/min. Therefore, optionally,
the fluid is infused into the region at 150 cc/min, 160 cc/min, 170
cc/min, 180 cc/min, 190 cc/min, 200 cc/min, 210 cc/min, 220 cc/min,
230 cc/min, 240 cc/min, 250 cc/min, 260 cc/min, 270 cc/min, 280
cc/min, 290 cc/min, 300 cc/min, 310 cc/min, 320 cc/min, 330 cc/min,
340 cc/min, 350 cc/min, 360 cc/min, 370 cc/min, 380 cc/min, 390
cc/min, 400 cc/min, 410 cc/min, 420 cc/min, 430 cc/min, 440 cc/min,
450 cc/min, 460 cc/min, 470, cc/min 480 cc/min, 490 cc/min, 500
cc/min, 510 cc/min, 520 cc/min, 530 cc/min, 540 cc/min, 550 cc/min,
560 cc/min, 570, cc/min 580 cc/min, 590 cc/min, 600 cc/min, or at
rates there between.
The catheter 104 used to deliver the fluid is introduced and
advanced through an artery of the subject. A venous catheter 102 is
also percutaneously introduced and advanced through the veins of
the subject to the region. The arterial 104 and venous 102
catheters can be placed in fluid communication within a HF-ILI
circuit.
Still referring to FIGS. 1A and 1B, example circuits comprise an
extra-corporal portion. The extra-corporal portion optionally
comprises tubing, valves, stop cocks and a syringe 114. The HF-ILI
circuits also comprise a corporal portion which includes the
terminal portions of the arterial and venous catheters and the
vasculature of the limb.
A full HF-ILI circuit allows for fluid comprising a therapeutic
agent 112 to enter the subject through the arterial catheter 104
and to be removed from the subject through the venous catheter 102.
The fluid (also referred to as an infusate) containing the
therapeutic agent, such as a chemotherapeutic agent, and the
patient's blood can be circulated into and out of the subject, e.g.
circulated through the circuit, using a fluid forcing device such
as the syringe 114.
The fluid circulated through the circuit can be heated using a
warming device such as a warming coil 118. The limb can also be
heated, for example, by using an external heater 124 and/or a
heating blanket 120. A variety of valves or three-way stop cocks
can be used to coordinate movement of fluid through the circuit.
These valves and/or stop cocks can be located at positions of the
circuit such as the junction 115 of a line 126 from the fluid
source and the extra-corporal circuit tubes or at the junction 116
of the syringe or pumping apparatus and the extra-corporal circuit.
For example, valves and/or stop cocks can be used to direct fluid
movement in a desired direction upon actuation of the syringe 114
or another pumping apparatus. The methods, systems and devices
described herein are not limited to circuits containing specific
features and one skilled in the art will appreciate that a variety
of circuit architectures can be used while providing HF-ILI flow
rates described herein.
To reduce or prevent systemic exposure to the therapeutic agent,
escape of the fluid from the region can be reduced or eliminated.
For example, a tourniquet 110 may be applied proximal to the
location where fluid is infused into the region from the arterial
catheter 104. The catheters each have a portion (105 and 107)
distal to the tourniquet.
Systemic exposure can be further reduced or eliminated by reducing
flow of infused fluid through one or more of the subject's
collateral vessels in the region. For example, selective
embolization can be used to eliminate or reduce flow through one or
more of the subject's collateral vessels in the region.
FIG. 2 is a schematic illustration of an example pump-assisted
HF-ILI circuit 200. Similar to the circuits described above, the
pump-assisted HF-ILI circuit shown in FIG. 2 is optionally used to
perform isolated limb infusion with a fluid comprising one or more
chemotherapeutic agents with infusion rates at or above 150
cc/min.
For example, using the system of FIG. 2 fluid, comprising a
chemotherapeutic agent, can be infused through a region of a
subject at a predetermined rate. The fluid is optionally infused
into the region at a rate of between 150 cc/min and 600 cc/min.
Therefore, optionally, the fluid is infused into the region at 150
cc/min, 160 cc/min, 170 cc/min, 180 cc/min, 190 cc/min, 200 cc/min,
210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min, 250 cc/min, 260
cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300 cc/min, 310 cc/min,
320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min, 360 cc/min, 370
cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410 cc/min, 420 cc/min,
430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min, 470, cc/min 480
cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520 cc/min, 530 cc/min,
540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min 580 cc/min, 590
cc/min, 600 cc/min, or at rates there between.
The circuit 200 includes a pump 202. The pump 202 includes and
inlet portion 204 and an outlet portion 216. The pump is used to
drive fluid through the circuit and through the region of the
subject that is to be treated by HF-ILI. For example, the pump is
optionally adjustable such that the rate of fluid flow through the
circuit is at least 150 cc/min and up to and including 600 cc/min,
for example.
As described herein, the term circuit can include portions of the
described devices positioned external to the subject being treated,
portions of the described devices positioned inside the subject,
and portions of the subject's vasculature. In use, all of these
portions allow for fluid to be circulated through the region of the
subject that is targeted for treatment, such as regions of the
subject afflicted with cancerous cells.
Optionally, the pump is a nonocclusive pump. Optionally, the pump
is a pressure differential pump. For example, a nonocclusive
centrifugal blood pump is optionally used. Such a pump promotes
laminar flow. The pump is optionally a Bio-Pump.RTM. (Medtronic,
Minneapolis, Minn.). For example, the pump is optionally a
Bio-Pump.RTM. Plus BPX80 or BPX50 nonocclusive pump. Optionally,
the pump is used with one or more of a Bio-Console.RTM. (Medtronic,
Minneapolis, Minn.) speed controller, a bubble detector cable, a
level sensor, a flow transducer, a dual channel pressure monitor,
an external drive motor, and a hand crank.
The pump optionally uses an AC power source and includes a
brushless DC pump drive motor. The pump can provide the desired
flow rates without causing collapse of the veins in which the large
bore venous catheters are located. For example, the pump can be
used to circulate fluid comprising a chemotherapeutic agent through
the vasculature of a subject at a rate of at least 150 cc/minute
using a venous catheter of 6 french or larger without causing
collapse of the vein that the catheter is inserted into. The pump
can be integrated with a console such as the Bio-Console.RTM.,
which can receive user input causing adjustment of operating
parameters of the pump. For example, the revolutions per minute of
the pump can be adjusted up or down to achieve a desired flow rate
between 150 cc/min and 600 cc/min. The fluid optionally comprises
blood, chemotherapy, and one or more carrier or diluents.
The catheters used are such as those described throughout. The
catheters can vary in length. For example, the catheters can be up
to sixty centimeters in length or longer. The length of the
catheters can be determined for example depending on factors such
as the region of the subject being treated and the size of the
subject. Such catheters are known in the art and, for example, are
used in interventional radiology procedures.
The portion of the circuit external to the subject includes a
venous segment (206, 208, 210, 212, and 214). Although not shown in
FIG. 2, the venous circuit can further include a catheter placed in
the subject and attached at 214. The venous catheter (not shown) is
attachable at the male luer 214, which itself is attached to the
medical grade fluid conduit segment 212. Optionally, the conduit
212 is medial grade tubing having predetermined dimensions of 3/16
inch internal diameter, by 1/16 inch wall thickness, by four or
more feet long. Other dimensions can also be used while still
allowing the desired flow rates.
The conduit segment 212 is attached to a linker segment 208 such as
a luer linker, which, in addition to the conduit segment 212,
allows passage of fluid there through. The linker segment 208 is in
fluid communication with a 3-way stop cock 210 that can be adjusted
to control fluid flow through the circuit and can also be used to
direct fluid flow out of the circuit, for example, to a pressure
detection device that can be used to detect and monitor pressure
within the circuit. For example, a Medtronic (Minneapolis, Minn.)
DLP or dual channel pressure monitor can be used. Pressure monitors
are optionally configured for use with the particular pump used in
the circuit. The venous segment further includes a conduit segment
206 that fluidly connects the linker segment to the inlet of the
pump 202.
The portion of the circuit external to the subject also includes an
arterial segment (218, 220, 222, 224, 226, 228, 232, 236, 230, 234,
238 and 240. The arterial segment is used to deliver fluid from the
pump into the arterial system of a subject. A conduit 218 is
attached to the outlet 216 to receive fluid delivered from the pump
202. The fluid moves through the conduit 218 and through a flow
probe 220. The flow probe 220 can be used to detect and/or monitor
fluid flow rate through the circuit. For example, the flow probe
can be used to indicate a flow rate of about 150 cc/min or higher.
The flow probe can be configured for use with the particular pump
used and thus be calibrated to provide accurate flow readings for
flow through the circuit.
A conduit 222 can be used to connect the flow probe to a linker
conduit segment 224 or linker luer, which is in fluid communication
with a 3-way stop cock 226. As described with respect to the venous
branch of the circuit, the 3-way stop cock 226 can be adjusted to
control fluid flow through the circuit and can also be used to
direct fluid flow out of the circuit, for example, to a pressure
detection device that can be used to detect and monitor pressure
within the circuit.
The arterial segment further includes a conduit segment 228 that
fluidly connects the linker segment to the inlet 232 of a heat
exchange unit 230. Fluid flows through the heat exchange unit 230
and exits at the outlet 234. As fluid flows through the heat
exchange unit, it can be warmed or cooled to a desired temperature.
For example, the fluid can be warmed to a desired temperature to
help maintain the limb at a desired treatment temperature. A
desired limb treatment temperature may, for example, be about 37 C.
In this regard, the fluid passing through the circuit can be warmed
above normothermic. For example, the fluid in the circuit is
optionally warmed at the heat exchange unit to temperatures above
37 C. For example, the heat exchange unit can be warmed to about 42
C causing warming of the fluid flowing there through to near 42 C.
The fluid flowing through the circuit optionally is warmed to
between 40 and 42 C.
Example heat exchangers include those for warming blood. For
example, optional heat exchangers include ECMO.RTM. (Medtronic,
Minneapolis, Minn.). The outlet 234 of the heat exchange unit is
attached to a conduit segment 238, which terminates in a male luer
240. The male luer can be attached to an arterial catheter as
described herein for delivering fluid into the arterial system of
the subject. A 3-way stop cock 236 may also be located at the heat
exchanger where it is optionally used to eliminate air from the
circuit.
The arterial catheter can further comprise one or more 3-way stop
cocks (244 and 242) integral with the male luer 240 or positioned
between the heat exchange unit and the male luer. The 3-way stop
cocks can be used to stop fluid flow through the circuit and to
push chemotherapeutic agent and flush agents into the circuit. For
example, the chemotherapeutic agent can be added to the system by
attaching the chemotherapeutic agent or source thereof to a stop
cock on the arterial side distal to the heat exchanger. The stop
cock is opened and the agent is pushed into the circuit. The stop
cock can be closed and another stop cock opened to push flush into
the circuit. The circuit can then be allowed to run for a given
duration and additional chemotherapeutic agent and flush can be
introduced into the circuit until the desired dosage has been
introduced into the circuit.
The circuit can be primed using gravity. For example, the stop
cocks at the male luers can be used to shut off circulation through
the circuit. An IV administration set with fluid can be attached to
the venous side of the circuit and the IV bag of the set can be
raised above the circuit. Then the stop cock at the arterial end
can be opened allowing the circuit to fill with fluid, such as
saline, before being attached to the venous and arterial catheters
which are previously positioned in the desired region of the
subject. Optionally, the venous and arterial catheters are placed
within the subject prior to connection to the external portions of
the circuit shown in FIG. 2. The full volume of the circuit is
optionally about 300 to 400 milliliters.
EXAMPLES
Example 1
High flow rate ILI is performed to regionally treat cancer in a
subject. A schematic overview of systems 100 and 101 for performing
the procedure are show in FIGS. 1A and 1B. Briefly, the technical
details are as follows: catheters 102 and 104 with additional
side-holes near their tips are inserted percutaneously into the
axial artery 104 and vein 102 of the disease-bearing limb 106 via
the contralateral groin 108, and their tips are positioned in such
a way that they are at the level of the knee or elbow joint. The
catheters are optionally greater than 6 french in size and the flow
rates are 150 cc/min or higher. Tissues more proximally located in
the limb but distal to the level of the tourniquet 110 are perfused
in a retrograde fashion via collateral vascular channel.
Prior to infusion and completing the closed circuit with the
catheters, the patient is given a general anesthetic, and heparin
(3 mg/kg) is infused to achieve full systemic heparinization.
Optionally, a single 5 mg IV dose of tropisetron, a 5HT3
antagonist, is administered as prophylaxis against postoperative
nausea and vomiting.
A pneumatic tourniquet 110 is inflated around the root of the limb
to be treated and the fluid 112 comprising a therapeutic agent,
such as a cytotoxic agent is infused into the isolated circuit via
the arterial catheter 104. Example cytotoxic drugs are melphalan
5-10 mg/l of tissue (e.g., 7.5 mg/l) and actinomycin-D 50-100
.mu.g/l of tissue (e.g., 75 .mu.g/l) in 400 mL warmed, heparinized
normal saline.
A dose of melphalan of about 7.5 mg/l volume lower extremity and 10
mg/l upper extremity can be used. The dosage can be adjusted based
on patient characteristics, such as those described above, one
example being ideal body weight. These principles are applied in
determining melphalan dosages for high flow rate ILI. Actinomycin-D
can be used as well because of the good response rates (CR 73%) of
the melphalan/actinomycin-D combination when administered by
conventional ILP.
For the duration of the high flow rate ILI procedure (20-30
minutes), the infusate is continually circulated by repeated
aspiration from the venous catheter 102 and reinjection into the
arterial catheter 104 using a syringe 114 attached to a three-way
tap 116 in the external circuit. During the procedure, fluid can be
infused at a predetermined rate. For example, the fluid is
optionally infused into the region at a rate of between 150 cc/min
and 600 cc/min. Therefore, optionally, the fluid is infused into
the region at 150 cc/min, 160 cc/min, 170 cc/min, 180 cc/min, 190
cc/min, 200 cc/min, 210 cc/min, 220 cc/min, 230 cc/min, 240 cc/min,
250 cc/min, 260 cc/min, 270 cc/min, 280 cc/min, 290 cc/min, 300
cc/min, 310 cc/min, 320 cc/min, 330 cc/min, 340 cc/min, 350 cc/min,
360 cc/min, 370 cc/min, 380 cc/min, 390 cc/min, 400 cc/min, 410
cc/min, 420 cc/min, 430 cc/min, 440 cc/min, 450 cc/min, 460 cc/min,
470, cc/min 480 cc/min, 490 cc/min, 500 cc/min, 510 cc/min, 520
cc/min, 530 cc/min, 540 cc/min, 550 cc/min, 560 cc/min, 570, cc/min
580 cc/min, 590 cc/min, 600 cc/min, or at rates there between.
Limb temperature is increased by incorporating a blood-warming coil
118 in the extracorporeal circuit and by encasing the limb in a
hot-air blanket 120, with a radiant heater placed over it.
After 20-30 minutes, the limb is flushed with one liter of
Hartmann's solution 122 via the arterial catheter 104, and the
venous effluent is discarded. For example, the limb can be infused
for 30 minutes prior to flushing. The limb tourniquet 110 is then
deflated to restore normal limb circulation, the heparin is
reversed with protamine, and the catheters are removed. For
patients with metastatic disease in the groin or axilla requiring a
regional lymph node dissection as well as a high flow rate ILI,
this can be undertaken under the same anesthetic after completion
of the high flow rate ILI procedure, removal of the catheters (102
and 104), and reversal of heparin.
Subcutaneous and intramuscular limb temperatures are monitored
continuously during the high flow rate ILI procedure, and blood
samples are optionally taken at regular intervals to measure the
melphalan concentrations and blood gases. The drug leakage rate
from the isolated limb into the systemic circulation is optionally
assessed retrospectively in all patients, on the basis of systemic
melphalan concentrations that can be measured routinely during each
procedure.
Example 2
Venous 102 and arterial 104 catheters are placed percutaneously in
a subject for regional treatment of cancer in a subject by high
flow rate isolated limb infusion (HF-ILI). The arterial catheter
104 can be greater than 6 french in size. For example, a 7 french
arterial catheter can be used. The venous catheter 102 can also be
6 french in size or greater. For example, a 7 french venous
catheter can be used.
The catheters (102 and 104) can be inserted percutaneuosly at a
site remote from the region to be treated. For example, an
ipsilateral popliteal or a contralateral femoral approach can be
used for treating an arm or a leg.
Flouroscopy can be used to navigate the catheters (102 and 104)
from the insertion site to the region to be treated. Optionally,
fluoroscopy times can be reduced using a popliteal approach. For
example, the time can be reduced from a median of 17.9 to 8.3
minutes; range (P=0.0019) resulting in significantly less exposure
to the radiologist and patient.
The HF-ILI circuit can further comprise one way valves and three
way stop cocks to control flow of fluid through the circuit. A
heating source 118 can be used to warm fluid in the circuit and a
heater 124 and a heating blanket 120 can be used to warm the limb
that is being treated. For example, a heating bath with an in-line
cardiac heat exchanger can be used to warm the fluid. The
temperature of the fluid can be monitored using a thermometer 126
that is within the circuit.
Optionally, the circuit comprises a perfusion machine to force
fluid through the circuit. A syringe or a pump can also be used to
force fluid through the circuit.
A tourniquet 110 can be applied to an extremity proximal to the
opening of the catheters in the region to be treated. The
tourniquet can be used to reduce systemic exposure of a therapeutic
agent, such as an anti-cancer drug. The tourniquet can be
optionally applied at 300 mmHg to a lower extremity and 250 mmHg to
an upper extremity. The patient can also be heparinized and the
patients ACT can be optionally calculated. For example, the patient
can be anticoagulated to an ACT over 400 seconds. The heparin can
be later reversed by protamine use.
The completed circuit is used to perform HF-ILI. For example, after
fully heparinizing the patient and then completing the circuit, the
circuit can be primed with blood. Once the tourniquet is applied
the subject's pedal pulse can be monitored to see that it
disappears. For example, Doppler can be used to determine if the
tourniquet has closed the artery supplying the limb. One skilled in
the art will appreciate that the pulse can be monitored in other
arteries supplying the limb to be treated. Next, 60 mg papaverine
can be infused through the arterial side, followed by an infusion
of chemotherapy. The fluid including chemotherapy can be circulated
through corporal and extra-corporal portions of the circuit for
about 30 minutes. The fluid can be infused at a predetermined rate.
For example, the fluid is optionally infused into the region at a
rate of between 150 cc/min and 600 cc/min. Therefore, optionally,
the fluid is infused into the region at 150 cc/min, 160 cc/min, 170
cc/min, 180 cc/min, 190 cc/min, 200 cc/min, 210 cc/min, 220 cc/min,
230 cc/min, 240 cc/min, 250 cc/min, 260 cc/min, 270 cc/min, 280
cc/min, 290 cc/min, 300 cc/min, 310 cc/min, 320 cc/min, 330 cc/min,
340 cc/min, 350 cc/min, 360 cc/min, 370 cc/min, 380 cc/min, 390
cc/min, 400 cc/min, 410 cc/min, 420 cc/min, 430 cc/min, 440 cc/min,
450 cc/min, 460 cc/min, 470, cc/min 480 cc/min, 490 cc/min, 500
cc/min, 510 cc/min, 520 cc/min, 530 cc/min, 540 cc/min, 550 cc/min,
560 cc/min, 570, cc/min 580 cc/min, 590 cc/min, 600 cc/min, or at
rates there between. The circuit can then be flushed and the
tourniquet can be released.
The described circuits in this example and through the
specification can be used to perform HF-ILI using minimally
invasive techniques. For example, the circuits can be used to treat
locally recurrent and metastatic melanoma isolated to one limb. The
catheters (102 and 104) are percutaneously introduced and
chemotherapy can be infused for about 30 minutes. Table 1 shows
some aspects of HF-ILI (left column) versus the more complicated
and expensive and medically risky procedure of isolated limb
perfusion (right column)
TABLE-US-00001 TABLE 1 Minimally invasive small Open surgical
procedure caliber percutaneously with large bore catheters, placed
catheters more complex Shorter operative and Longer operative and
perfusion times perfusion times Hypoxic, acidotic conditions
Aerobic, oxygenated High flow High flow Mild hyperthermia
Hyperthermia Easy to repeat procedure Difficult to repeat
Dosing for HF-ILI can be determined using factors such as water
displacement and serial circumferential measurements. Dosing is
optionally corrected for ideal body weight (cIBW). Example dosing
of Melphalan is 7.5 mg/l for a lower extremity and 10 mg/l for an
upper extremity. An example dose of Actinomycin D is 100 ug/l for
both a lower and upper extremity.
As described, the systems, methods and devices described herein can
be used to treat regional cancer. An example cancer that can be
treated is melanoma. Other example cancers that can be treated are
an unresectable sarcoma, a Merkel cell carcinoma, advanced SCCA,
and adnexal skin cancers.
Many modifications and other embodiments of the invention set forth
herein will come to mind to one skilled in the art to which this
invention pertains having the benefit of the teachings presented in
the foregoing description. Therefore, it is to be understood that
the invention is not to be limited to the specific embodiments
disclosed and that modifications and other embodiments are intended
to be included within the scope of the appended claims. Although
specific terms are employed herein, they are used in a generic and
descriptive sense only and not for purposes of limitation.
* * * * *